CF is caused by defects in both copies of the CFTR gene. The gene encodes for a protein called cystic fibrosis transmembrane conductance regulator, which transports chloride ions across cell membranes.
CFTR gene mutations lead to faulty versions of the CFTR protein, which prevents chloride ions from being sent through the body. Because the ions are necessary for fluid balance in the lungs, the imbalance that occurs there leads to cystic fibrosis.
How GLPG2222 works
GLPG2222 is what scientists call a corrector because it fixes the defective CFTR protein by restoring its folding and stability.
GLPG2222 in clinical trials
Researchers conducted a Phase 1 clinical trial (NCT02662452) to evaluate GLPG2222’s safety and pharmacokinetics, or movement through the body. Healthy volunteers received single and multiple ascending doses of the therapy.
The trial showed that GLPG2222 was safe and that participants tolerated it well, with researchers finding only mild side effects. The body absorbed the drug rapidly, a sign that it would be able to do its job.
Another Phase 1 trial (NCT02788721) compared a combination of GLPG2222 and another Galapagos therapy, GLPG2451, with GLPG2451 as a stand-alone treatment. It involved 40 healthy people in Belgium. Researchers looked at the safety and pharmacokinetics of single and multiple ascending doses of the combo and GLPG2451 alone.
GLPG2451 is a CFTR potentiator — that is, it increases the defective protein’s activity.
Galapagos conducted a Phase 2a clinical trial (NCT03045523) to evaluate GLPG2222’s safety and cystic fibrosis patients’ ability to tolerate it. The 37 patients had a gating mutation and were on Vertex Pharmaceuticals’ Kalydeco (ivacaftor). During the trial they received one of two doses of GLPG2222 or a placebo once a day for 28 days.
The results showed that GLPG2222 was safe and that patients tolerated it well, with side effects being mild. Patients displayed a dose-dependent increase in lung function from treatment, meaning that the larger the dose, the more benefit. The lung-function yardstick that researchers used was forced expiratory volume in one second, or FEV1. That is the amount of air a person can exhale in one second after taking a deep breath. Patients who took GLPG2222 had higher FEV1 scores.
Patients also experienced statistically significant dose-dependent decreases in sweat chloride. People with cystic fibrosis get rid of a lot of chloride in their sweat, which means that sweat chloride is a biomarker of the disease’s severity. So a decrease in sweat chloride indicated that GLPG2222 was benefiting patients.
The bottom line on the trial was that GLPG2222 offered clinical benefits beyond those that Kalydeco offered, researchers said.
Another Phase 2a trial (NCT03119649) assessed GLPG2222 as a treatment for cystic fibrosis patients whose disease stemmed from an F508del gene mutation. The treatment lasted four weeks. The study was completed in October 2017, but Galapagos has yet to release results.
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